RESUMEN
AZD0530, an orally available Src inhibitor, demonstrated potent antimigratory and anti-invasive effects in vitro, and inhibited metastasis in a murine model of bladder cancer. Antiproliferative activity of AZD0530 in vitro varied between cell lines (IC(50) 0.2 ->10µM). AZD0530 inhibited tumor growth in 4/10 xenograft models tested and dynamically inhibited in vivo phosphorylation of Src substrates paxillin and FAK in both growth-inhibition-resistant and -sensitive xenografts. The activity of AZD0530 in NBT-II bladder cancer cells in vitro was consistent with inhibition of cell migration and stabilization of cell-cell adhesion. These data suggest a dominant anti-invasive pharmacology for AZD0530 that may limit tumor progression in a range of cancers. AZD0530 is currently in Phase II clinical trials.
Asunto(s)
Antineoplásicos/farmacología , Benzodioxoles/farmacología , Proteínas de Neoplasias/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto , Familia-src Quinasas/antagonistas & inhibidores , Administración Oral , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ensayos Clínicos Fase II como Asunto , Quinasa 1 de Adhesión Focal/metabolismo , Humanos , Ratones , Ratones Desnudos , Células 3T3 NIH , Invasividad Neoplásica , Proteínas de Neoplasias/metabolismo , Trasplante de Neoplasias , Paxillin/metabolismo , Fosforilación/efectos de los fármacos , Ratas , Ratas Desnudas , Trasplante Heterólogo , Neoplasias de la Vejiga Urinaria/enzimología , Neoplasias de la Vejiga Urinaria/patología , Familia-src Quinasas/metabolismoRESUMEN
A series of 5,7-disubstituted quinazolines, bearing 4-heteroaryl substituents such as 2-pyridinylamine or 2-pyrazinylamine, has been synthetised and evaluated as c-Src kinase inhibitors. Highly potent inhibition, high selectivity and physical properties suitable for oral dosing were achieved within this series: 23d and 42 were identified as sub-0.1muM inhibitors in a c-Src-driven cell proliferation assay and displayed adequate rat pharmacokinetics after oral administration.